Systemic lupus erythematosus (SLE) is a prototypic systemic autoimmune disease with gender-bias affecting mostly women of childbearing age. The basis of the gender bias remains to be elucidated. In this proposal, significant preliminary data to support the preferential expression of estrogen receptor (ER)b by T cells from SLE patients provide the basis to explore the role of interactions of estrogen and its receptors in the pathogenesis of SLE and its predilection for females. Three specific aims are proposed. Specific Aim 1 will examine the protein and mRNA expression of ERa and ERb in circulating T cells of patients with SLE in comparison with healthy Controls to establish that there is preferential expression of ERb by T cells isolated from SLE patients and to determine the basis for this preferential expression. Specific Aim 2 will determine if ER activation differs in T lymphocytes from SLE patients and controls and to determine whether altered sensitivity of T cells from SLE patients and certain normal control populations is due to the effects of proteins which regulate ER activity. Specific Aim 3 will compare ER function between the normal strains and autoimmune-prone strain NZM2328, and to generate ERa-/- and ERb-/- mutants in NZM2328 background and to phenotype these mutants for autoantibody production and the induction of acute and chronic glomerulonephritis. Under the direction of this project, the U.Va Lupus Cohort Database is maintained for the use by SCOR investigators. The results of these experiments will provide further insight into the mechanisms of sex hormone influence in autoimmunity and the basis for the gender-bias in this disorder. In addition, they might also provide the rationale for hormonal ablation as an adjunct therapy for SLE.